Leiden University Scholarly Publications

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Chen, L. (2023)

Optimizing antifungal treatment through pharmacometrics: dosing considerations to enhance outcome

Doctoral Thesis
Fungal infections pose a significant threat to individuals with compromised immune systems and despite advancements in diagnosis and treatment, they continue to jeopardize patient’s health. Maximizing the effectiveness of existing antifungal drugs is imperative. Among these, fluconazole and posaconazole are commonly prescribed to treat severe and life-threatening fungal infections. In this thesis, among others, we aimed to understand better how well different posaconazole formulations are absorbed. Through computational modeling and simulation, we learned that posaconazole is best taken with food to reduce the risk of inadequate drug absorption and subsequent therapeutic failure. This applies not only to the suspension but also to the tablet, which results in higher and more predictable absorption even though it does not achieve concentrations similar to those upon intravenous administration. Fluconazole was studied in individuals with obesity. Our findings indicate that heavier...Show more

Fungal infections pose a significant threat to individuals with compromised immune systems and despite advancements in diagnosis and treatment, they continue to jeopardize patient’s health. Maximizing the effectiveness of existing antifungal drugs is imperative. Among these, fluconazole and posaconazole are commonly prescribed to treat severe and life-threatening fungal infections. In this thesis, among others, we aimed to understand better how well different posaconazole formulations are absorbed. Through computational modeling and simulation, we learned that posaconazole is best taken with food to reduce the risk of inadequate drug absorption and subsequent therapeutic failure. This applies not only to the suspension but also to the tablet, which results in higher and more predictable absorption even though it does not achieve concentrations similar to those upon intravenous administration. Fluconazole was studied in individuals with obesity. Our findings indicate that heavier adult males may require a higher dose to achieve the desired exposure. Consequently, we proposed dosing recommendations for treating obese patients.

In summary, this research, a result of the long-term collaboration between Leiden University and Radboudumc, enhanced our knowledge of factors that reduce exposure to antifungal drugs, allowing us to guide how to individualize and optimize antifungal treatment in individual patients.

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Posaconazole
Fluconazole
Formulation
Pharmacokinetics
Oral bioavailability
Nonlinearity
Healthy volunteers
Hematology patients
Obese
Chinese
All authors
Chen, L.
Supervisor
Knibbe, C.A.J.
Co-supervisor
Krekels, E.H.J.; Brüggemann, R.J.
Committee
Irth, H.; Lange, E.C.M. de; Svensson, E.M.; Hasselt, J.G.C. van; Verweij, P.E.
Qualification
Doctor (dr.)
Awarding Institution
Leiden Academic Centre for Drug Research (LACDR), Faculty of Science, Leiden University
Date
2023-12-19
ISBN (print)
9789464835656

Funding

Sponsorship
China Scholarship Council